PROJECT SUMMARY/ABSTRACT Research supports the feasibility of active surveillance (AS) strategies for clinically localized prostate cancer, but lack of discriminating markers at diagnosis and the diverse clinical response of morphologically identical tumors stymie treatment planning and frustrate patients. Safely expanding the number of patients with indolent disease participating in AS, reducing unnecessary biopsies, and ultimately avoiding unnecessary definitive radical treatments associated with significant morbidities, including impotence and incontinence, are critical challenges. At the same time, determining the optimal definitive therapy for early aggressive disease remains imperative. We will test a theory that adaptive metabolic reprogramming as reflected in an increase in de novo lipid synthesis drives the transition from indolent to aggressive prostate cancer. The hypotheses to be tested are that during early prostate cancer?s transition from indolent to aggressive disease, caveolin-1 (Cav-1)- induced plasma levels of specific lipids, including glycosphingolipids and a sphingomyelin signature that can be measured in a ?liquid biopsy,? will provide predictive information about the transition from indolent to aggressive prostate cancer. Our overriding objective is to develop a liquid biopsy that will be able to distinguish indolent from aggressive disease. Successful completion of this project will increase understanding of the molecular and cellular characteristics distinguishing indolent from aggressive lesions, help create reliable frameworks for predicting disease progression in men with early prostate cancer, and lay groundwork for a R01 proposal with methods to refine risk stratification of early prostate cancer and obviate prostate biopsies. To achieve these outcomes, we will pursue two Specific Aims. First, we will evaluate Cav-1- induced lipid metabolites and their biological activities in prostate cell lines. Since our hypothesis is that some biomarkers or a combination of biomarkers will differ between cases and controls, we will test using liquid chromatography?tandem mass spectrometry metabolomics (sphingolipids and glycolipids as well as other lipid metabolites) to distinguish indolent from aggressive prostate cancers. Second, we will characterize the candidate lipid metabolites in archived plasma specimens from an active surveillance prostate cancer cohort. Our innovative integration of state-of-the art molecular platforms and modeling of biological processes is expected to uncover mechanisms underlying the transition in early prostate cancer from indolent to aggressive disease and yield a liquid biopsy that once validated in a large study will transform early prostate cancer management.